PDF: ECASS III
(2008)Objective
To evaluate the efficacy and safety of intravenous alteplase (tPA) administered 3 to 4.5 hours after symptom onset in patients with acute ischemic stroke.
Study Summary
Intervention
Alteplase (0.9 mg/kg IV, max 90 mg; 10% as bolus and rest over 60 minutes) vs. placebo, administered between 3 and 4.5 hours after stroke onset.
Inclusion Criteria
Patients aged 18–80 with acute ischemic stroke and measurable neurological deficit, treated between 3 and 4.5 hours of symptom onset. Key exclusions included severe stroke (NIHSS >25), prior stroke and diabetes, or oral anticoagulant use.
Study Design
Arms: Alteplase vs. Placebo
Patients per Arm: Alteplase: 418, Placebo: 403
Outcome
Bottom Line
Alteplase given between 3–4.5 hours after stroke significantly improved functional outcomes but increased the risk of symptomatic intracranial hemorrhage, with no difference in mortality.
Major Points
- Landmark randomized, double-blind, placebo-controlled trial that extended the IV alteplase treatment window from 3 to 4.5 hours after stroke onset.
- 821 patients randomized 1:1 across 130 centers in 19 European countries. Median onset-to-treatment time: 3 hours 59 minutes.
- Primary outcome (mRS 0–1 at 90 days): 52.4% vs 45.2% (OR 1.34, 95% CI 1.02–1.76, P=0.04, NNT 14).
- Global outcome (composite mRS, BI, NIHSS, GOS): OR 1.28 (95% CI 1.00–1.65, P=0.05) — borderline significant.
- Symptomatic ICH (per ECASS definition): 2.4% vs 0.2% (P=0.008). Any ICH: 27.0% vs 17.6% (P=0.001).
- 90-day mortality: 7.7% vs 8.4% (P=0.68) — no difference despite higher ICH rate.
- Alteplase dose: 0.9 mg/kg (max 90 mg), 10% bolus + 90% over 60 minutes — same NINDS protocol.
- Notable exclusion: patients with combination of prior stroke AND diabetes were excluded (concern for higher ICH risk), limiting generalizability to this common subgroup.
- Led to AHA/ASA guideline update recommending IV alteplase up to 4.5 hours (Class I, Level B). FDA never formally approved the extended window, but 3–4.5h became standard of care.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 821
- Follow-up
- 90 days
- Centers
- 130
- Countries
- Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Netherlands, Norway, Poland, Portugal, Slovakia, Spain, Sweden, Switzerland, United Kingdom
Primary Outcome
Definition: mRS 0–1 at 90 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 45.2% | 52.4% | - (1.02–1.76) | 0.04 |
Limitations & Criticisms
- Modest absolute benefit (NNT=14) compared to NINDS (NNT=8) — reflects diminishing returns of later treatment.
- Upper age limit of 80 years — excluded elderly patients who represent a large proportion of real-world stroke patients (later addressed by IST-3).
- NIHSS cap at 25 — excluded very severe strokes.
- Exclusion of patients with combined prior stroke AND diabetes is clinically limiting — this is a common combination in stroke populations.
- Global outcome composite was only borderline significant (P=0.05) — raises questions about robustness.
- Higher sICH rate (2.4% vs 0.2%) — although not offset by mortality increase, still a concern.
- Industry-funded (Boehringer Ingelheim) — alteplase manufacturer.
- FDA never approved the 3–4.5h window despite guideline adoption — regulatory gap persists.
- No vascular imaging required — vessel occlusion status unknown, no ability to assess for LVO vs small vessel.
Citation
N Engl J Med 2008;359:1317-1329